Psychosocial Implications of Tardive Dyskinesia in Patients With Mood Disorders Versus Schizophrenia

Based on Stahl.²

First-Generation Antipsychotic Medications

FGA medications, such as chlorpromazine and haloperidol, are strong dopamine D2 receptor blockers and first became available in the 1950s.³ Initially, FGAs were prescribed to treat people with schizophrenia and severe variants of bipolar disorder, such as those with psychotic features or whose illness was refractory to agents like lithium. However, the efficacy of these FGAs was incomplete, as many patients had persistent positive psychopathology often accompanied by aggression, violence, self-injury, and suicide attempts.

When FGAs first became available, the dose-response relationship was not fully understood. It is now known that higher doses of FGAs do not result in increasing therapeutic benefits: the therapeutic effect climbs quickly and then levels off.⁴ However, increasing FGA doses produces more severe extrapyramidal movement-related adverse effects.⁵ At the time, clinicians used high doses and accepted the coarse extrapyramidal side effects (ie, movements that were obvious even to lay people) as necessary to reduce positive psychopathology.³ The D2 dopamine receptors targeted by FGAs reacted to dopamine deprivation by becoming hypersensitive, excessively reactive, and capable of initiating abnormal involuntary movements, ie, tardive dyskinesia (TD). With patients’ prolonged exposure to excessive doses of FGAs, TD became common, severe, and often grossly disfiguring.

To counter acute extrapyramidal side effects, clinicians prescribed anticholinergic medications.⁶ However, anticholinergic medications only mask extrapyramidal side effects. They do not alleviate the underlying alterations in the motor circuits, nor do they offer protection from the development—nor alleviate the severity—of TD.

Second-Generation Antipsychotic Medications

A major shift occurred with the development of SGA medications. Clozapine was first available in the United States in the 1980s and was efficacious against positive psychopathology and agitation in patients who had treatment-resistant positive and affective psychopathology and agitation. In addition, clozapine did not produce extrapyramidal effects, including TD. Early studies showed that clozapine relieved severe forms of TD that appeared with FGAs.⁷ However, clozapine has multiple significant side effects, including agranulocytosis and myocarditis, that complicate its use.⁸

Clozapine blocks serotonin from the 5HT2 receptor, which lessens the capacity of dopamine receptor blockade to produce coarse extrapyramidal effects. Subsequent SGAs were developed to mimic the strong 5HT2 receptor blockade of clozapine but coupled with either a lower dopamine D2 receptor blockade due to low dosing (as with low-dose risperidone or olanzapine) or a dopamine D2 partial agonism that protected the D2 receptors from dopamine storms while delivering a physiological level of dopamine receptor stimulation (as with aripiprazole). As a result, SGAs produce fewer and less severe early extrapyramidal adverse effects, resulting in fewer, and less often severe, cases of TD.

Expanded Use of SGAs

Clinicians recognize the improved tolerability of SGAs for the treatment of affective disorders. In manic and depressive exacerbations of bipolar disorder, augmentation of a mood stabilizer, such as lithium, with a low-dose SGA has led to more rapid remission and a greater percentage of patients achieving remission.⁹ In maintenance treatment of bipolar disorder, augmentation with a low-dose SGA delays or prevents relapse versus treatment with a mood stabilizer alone.¹⁰ In patients with recurrent major depressive disorder who have had an inadequate therapeutic response to antidepressants, augmentation with a low-dose SGA significantly increases the likelihood of remission versus treatment with antidepressants alone.¹¹

Treatment algorithms for bipolar disorder and depression now make low-dose SGAs a second step after initial lithium treatment for bipolar disorder or antidepressant treatment for major depression.^12,13 While TD occurs less frequently and is less severe in patients treated with the SGAs than FGAs, the risk is not zero.¹⁴ Estimates of annualized TD incidence are 6.5% with FGAs and 2.6% with SGAs.¹⁵ Because the risk of TD was not eliminated with SGAs, and because the SGAs are prescribed for more patients than the FGAs were, TD is still a common occurrence; clinicians must educate patients about and monitor for early signs of TD.

Tardive Dyskinesia in Patients With Schizophrenia and Severe Bipolar Disorder

Many patients with schizophrenia and some with severe bipolar disorder demonstrate multiple deficits in addition to psychosis and agitation. These deficits can include negative psychopathology, neurologic soft signs, and a lack of insight into their illness (AV 2).^16–19 Fixed deficits are associated with reduced brain volume and poor occupational and social functioning.²⁰ Dopamine receptor–blocking agents offer no therapeutic benefit for fixed deficits. Tardive dyskinesia is more common and severe in patients with fixed deficits; nevertheless, these patients tend to be unaware that they have abnormal involuntary movements, in the same way that they are unaware of their mental illness and need for treatment.²¹

AV 2. Deficits That May Be Experienced Among People With Schizophrenia or Severe Bipolar Disorder

In patients with lack of insight into the presence of TD, motivation to treat it is determined primarily by the Abnormal Involuntary Movement Scale (AIMS) exam,²² specifically items 8 (severity of abnormal movements overall) and 9 (incapacitation due to abnormal movements). Family members or other significant people in the patient’s life may also advocate for treatment. If the movements are disfiguring or interfere with the patient’s basic functioning (ie, eating, ambulation, breathing), clinicians should aggressively treat patients even if they are unaware of the movements or express little distress about them.

Case Practice Question 1

Bob is a 55-year-old man who was diagnosed with schizophrenia in his 20s. He has a history of negative psychopathology, has little insight to his illness, and has been taking depot haloperidol for several years. Recently, his family noticed him slurring his speech and moving his hands frequently as if he is “playing a piano.” They thought initially that he was inebriated, but the movements are now so severe that they are interfering with Bob’s daily functioning.

On the Abnormal Involuntary Movement Scale, you note that Bob’s “severity of abnormal movements overall” is severe, and his “incapacitation due to abnormal movements” is severe also. However, Bob reports no distress. What would be the best next step?

1. As Bob is not bothered by his TD, continue haloperidol and monitor for worsening symptoms
2. Continue haloperidol and add an FDA-approved treatment for TD
3. Discontinue haloperidol and switch to a second-generation antipsychotic
4. Discontinue haloperidol and avoid using another antipsychotic altogether

 Discussion of Case Practice Questions

Preferred response:  C. Discontinue haloperidol and switch to a second-generation antipsychotic
Explanation: Long-term use of first-generation antipsychotics like haloperidol is associated with a higher incidence of TD than second-generation antipsychotics (SGAs). Switching the haloperidol to an SGA might lessen his TD symptoms,²³ but Bob may also need treatment with an FDA-approved medication for TD.^24,25 Even though Bob is not distressed by his TD, it should be treated aggressively because his functioning is being impaired.

Case Practice Question 2

Sara is a 32-year-old woman in sustained remission of bipolar I disorder, taking lithium carbonate 300 mg bid and perphenazine 8 mg at bedtime for the past 5 years. She works as a teller at a local bank and has recently married. She reports having involuntary blinking and protrusion of her tongue for the past month. Her husband and a coworker have asked her about these movements. Your evaluation determines that Sara is experiencing tardive dyskinesia. Which of the following choices would be the best next step?

1. Ask Sara if she’s disturbed by the movements or worried about them affecting her job or new marriage
2. Inform Sara that her treatment regimen can be adjusted so that the movements are cured
3. Advise Sara that no treatment is needed because the movements are mild and do not affect functioning

 Discussion of Case Practice Questions

Preferred response: A. Ask Sara if she’s disturbed by the movements or worried about them affecting her job or new marriage
Explanation: Tardive dyskinesia and extrapyramidal effects are listed in the package insert for perphenazine.²⁹ Older female patients appear to have the highest risk, but onset can occur in younger patients and in children. The risk of TD increases with longer antipsychotic treatment duration. The FDA also notes extrapyramidal symptoms as a potential adverse drug interaction in lithium treatment when coupled with an antipsychotic.³⁰ Sara’s perphenazine and lithium regimen could be altered, but because her bipolar disorder is in remission, a better choice may be to offer treatment for TD with FDA-approved medications.^22,24 Because Sara has insight into her illness and is aware of her TD symptoms, which could interfere with her job working with the public, treatment decisions should be made in consultation with her.²⁵

Abbreviations

AIMS = Abnormal Involuntary Movement Scale
FDA = US Food and Drug Administration
FGA = first-generation antipsychotic
SGA = second-generation antipsychotic
TD = tardive dyskinesia

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